The central objective of this proposal is to contribute to the development of an understanding of the physical basis for protein-protein interactions. Coiled-coils are the subject of the proposal, which has a particular emphasis on the structural determinants of homodimer and heterodimer formation amongst this important and common class of protein-protein complexes. An array of techniques is to be employed including x-ray crystallography, computational methods, thermodynamic analysis and genetic screens. The proposal seeks to characterize the role of buried polar interactions in delineating the specificity of coiled-coil interactions; to extend a recently developed computational algorithm for sidechain repacking in an effort to efficiently explore the parameters that affect the thermodynamics of partnering; to undertake a database analysis of sequence determinants of partnering with an ultimate aim of developing algorithms that will faithfully reveal such interactions; and to test and extend existing knowledge about coiled-coil interactions by analyzing partnering at a genomic level using a yeast-based experimental system.